Intraocular pressure (IOP) and age were found to be the most consistent independent risk factors for development and progression of glaucoma in all of the major prospective clinical trials, even though IOP has not been shown to increase with age in most populations. Glaucoma is also much more prevalent in persons of African ancestry. Lowering IOP is the only clinical treatment that has been shown to retard the onset and progression of glaucoma, but once damaged, the optic nerve head (ONH) is thought to be more susceptible to further glaucomatous progression even after clinical intervention has lowered mean IOP to `normal' levels. We have previously interpreted these findings to mean that the ONH is increasingly vulnerable to glaucomatous injury with advancing age, African ancestry, and prior damage. There is a plausible alternative explanation, however. Our telemetric IOP data show that the eye is subjected to about 7,000 IOP spikes >5 mmHg per hour during waking hours. Also, IOP spikes >1 mmHg above baseline are responsible for up to 15% of the total IOP insult the eye must absorb during waking hours on average. This is an extraordinary finding, in that IOP spikes represent a previously unknown and potentially highly injurious component of the IOP total insult that has yet to be characterized or considered in previous animal or clinical studies. We hypothesize that greater IOP and ocular perfusion pressure (OPP) fluctuation independently contribute to the onset and progression of glaucoma in addition to mean IOP. We will test this organizing hypothesis by elucidating the age- and disease-related changes in IOP, OPP, and their fluctuations as they relate to retinal ganglion cell (RGC) axon loss and elevated IOP-induced ocular coat stiffening. Support for the fluctuation hypothesis would lead to an entirely new understanding of the importance of IOP and OPP fluctuation in the increased age- and disease-related susceptibility to glaucoma and provide strong rationale for totally new clinical diagnosis and treatment modalities that employ IOP and OPP fluctuation reduction through modification of ocular coats stiffness or intraocular damping of IOP fluctuations. If our results do not support the fluctuation hypothesis, the knowledge we gain about the natural fluctuations of these variables will redefine the appropriate IOP measurement frequency in patients and inform patient care.